Lindholm Dan, Mäkelä Johanna, Di Liberto Valentina, Mudò Giuseppa, Belluardo Natale, Eriksson Ove, Saarma Mart
Medicum, Department of Biochemistry and Developmental Biology, Medical Faculty, University of Helsinki, P.O.Box 63, 00014, Helsinki, Finland.
Minerva Medical Research Institute, Biomedicum-2 Helsinki, Tukholmankatu 8, 00290, Helsinki, Finland.
Cell Mol Life Sci. 2016 Apr;73(7):1365-79. doi: 10.1007/s00018-015-2101-1. Epub 2015 Nov 30.
Parkinson's disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.
帕金森病（PD）是一种进行性神经退行性疾病，其特征是中脑多巴胺能和非多巴胺能神经元发生变性和死亡，导致运动功能障碍及其他症状，严重影响帕金森病患者的生活质量。左旋多巴药物可缓解帕金森病的运动症状，但迄今为止，尚无针对潜在神经退行性病变过程的合理治疗方法。尽管进行了深入研究，但导致神经元丢失的分子机制仍未完全明确，这阻碍了新药和疾病修饰疗法的开发。神经营养因子凭借其促进存活的活性，成为对抗并可能阻止帕金森病细胞变性的候选物质。特别是，使用胶质细胞源性神经营养因子（GDNF）及其家族成员神经营养素（NRTN），以及最近描述的脑源性多巴胺神经营养因子（CDNF）和中脑星形胶质细胞源性神经营养因子（MANF）的研究，在帕金森病的各种模型中，已显示出在保护和修复多巴胺能神经元方面取得了积极成果。其他对多巴胺能神经元具有营养作用的物质包括神经肽和小分子化合物，它们作用于帕金森病中受损的不同途径，如细胞应激增加、蛋白质处理缺陷、线粒体功能障碍和神经炎症。在本综述中，我们将重点介绍该领域的最新进展，重点关注神经营养因子和在帕金森病临床前或动物模型中已显示出对多巴胺能神经元的活力和功能具有有益影响的物质。
